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Coagulopathy secondary to vitamin K deficiency caused by severe diarrhea
Coagulopathy Secondary to Vitamin K Deficiency Caused by Severe Diarrhea Catherine Kelly DO, Steven Sattler DO, Adam Schwartz DO PII: DOI: Reference:
S0735-6757(14)00762-1 doi: 10.1016/j.ajem.2014.10.028 YAJEM 54578
To appear in:
American Journal of Emergency Medicine
Received date: Accepted date:
15 September 2014 11 October 2014
Please cite this article as: Kelly Catherine, Sattler Steven, Schwartz Adam, Coagulopathy Secondary to Vitamin K Deficiency Caused by Severe Diarrhea, American Journal of Emergency Medicine (2014), doi: 10.1016/j.ajem.2014.10.028
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title: Coagulopathy Secondary to Vitamin K Deficiency Caused by Severe Diarrhea.
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Authors: Catherine Kelly, DOa, Steven Sattler, DOa, Adam Schwartz, DOa a Good Samaritan Hospital Medical Center, 1000 Montauk Highway, West Islip, NY 11795
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Keywords: coagulopathy; vitamin K deficiency; diarrhea
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Corresponding author: Catherine Kelly [email protected]; Good Samaritan Hospital Medical Center 1000 Montauk Highway, West Islip NY 11795; +16313764163
DIARRHEA INDUCING ACUTE VITAMIN K COAGULOPATHY
ACCEPTED MANUSCRIPT Introduction:
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We describe a woman who presented to the emergency department (ED) due to severe diarrhea who had a significant coagulopathy secondary to depletion of vitamin K dependent clotting factors.
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Case:
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A 31 year old female currently under treatment for gastric cancer presented to the ED complaining of generalized weakness associated with abdominal cramping. The patient had been experiencing generalized, severe abdominal cramping, nausea, and diarrhea for the previous two weeks. Her bowel movements were profuse watery diarrhea and had increased in frequency and volume in the preceding days.
ED
MA
These symptoms began soon after initiation of chemotherapy with 5-fluorouracil and folinic acid for gastric carcinoma. She had a partial gastrectomy three months prior to presentation as the initial treatment of this malignancy. The patient was also four days post-op from an uncomplicated dilation and curettage for a missed abortion. At the time of the obstetrical procedure all laboratory tests, including coagulation studies, were known to be within normal limits.
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The patient had no other significant chronic medical problems. Outpatient medications were limited to ondansetron and oxycodone prescribed after her dilation and curettage. The review of systems was pertinent for generalized weakness, nausea, diarrhea and abdominal pain. The patient denied any history of bruising, bleeding, petechiae or heavy menses. She denied any recent fevers or illness.
AC
The patient was afebrile with a pulse of 128, blood pressure of 124/88 mm Hg, respirations of 24 and a room air oxygen saturation of 99%. She appeared weak, diaphoretic and uncomfortable. Her abdomen was soft and tender to palpation periumbilically without guarding, rigidity, rebound, palpable organomegaly or masses. No skin lesions were noted. The remainder of physical exam was unremarkable. Morphine and ondansetron were administered for symptomatic relief. Laboratory results are listed in Table 1. A CT scan of the abdomen and pelvis with oral and intravenous contrast demonstrated no acute pathology. The patient was admitted to the intensive care unit with a metabolic acidosis, dehydration, and a profound coagulopathy. Her INR decreased from 11.2 to 1.7 within 24 hours after receiving 10 mg of phytonadione and 6 units of fresh frozen plasma. Mixing studies were performed which demonstrated full correction of the PT and PTT with dilution that was not time-dependent, ruling out presence of a clotting pathway inhibitor. The acidosis improved following rehydration and electrolyte replacement. She was treated with imipenem/cilastatin and metronidazole for presumed sepsis. All blood, stool and urine culture
ACCEPTED MANUSCRIPT results were negative. Over six days, the patient improved significantly and was subsequently discharged home for outpatient follow up with oncology.
T
Discussion:
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Our case demonstrates a patient with the abrupt onset of a coagulopathy consistent with vitamin K deficiency. The coagulopathy was thought to be multifactorial due in part to malabsorption of dietary vitamin K and disruption of the normal gut flora which synthesize it due to chemotherapy related diarrhea.
MA
NU
SC
Vitamin K is a cofactor in multiple steps of the coagulation cascade. It is required for the synthesis of factors II, VII, IX and X. It impacts the intrinsic, extrinsic and common clotting pathways. Approximately 50% of vitamin K is obtained dietarily with absorption of phylloquinone (vitamin K1) in the proximal intestine and menadione and menaquinone (vitamin K2) absorbed in the lower intestine and colon. The remaining 50% is produced via bacterial synthesis by the gut flora [1]. Unlike most other vitamins, vitamin K is not stored in the body to any significant extent and it is estimated that a healthy person’s physiologic reserve is adequate for only one week.
PT
ED
Our patient developed a severely elevated PT and INR with mild elevation in PTT that was consistent with severe vitamin K deficiency. This condition was further supported by full correction of the PT/INR with mixing studies and clinical correction after receiving vitamin K. The patient’s PT/INR was known to be normal 4 days prior to this ED evaluation at the time of her D&C, which is supportive that this was an acute process and not a chronic condition.
AC
CE
We believe her acute coagulopathy was not part of a sepsis syndrome because she remained afebrile without leukocytosis and negative cultures. Disseminated intravascular coagulation related to the recent missed abortion was ruled out because of elevated fibrinogen, normal platelets, and only mild elevation of the PTT. Development of vitamin K related coagulopathy secondary to diarrhea has long been recognized in pediatrics. Children with acute and intractable diarrhea have been shown to have increased PT and higher rates of clinically significant hemorrhage [2]. These symptoms may be related to inadequate intake, insufficient absorption and/or decreased synthesis due to changes in gut flora. However, this phenomenon has not been well described in the adult patients. Patients with chronic gastrointestinal disorders such as Crohn’s disease, may develop coagulopathy, but it typically requires a more prolonged course. Studies show that up to 46% of patients with untreated Crohn’s disease have mild vitamin K deficiency, while 18.5% have prolongation of PT [3,4]. In adults, case reports show development of similar coagulopathy has occurred in patients with hyperemesis gravidarum, pancreatic insufficiency, and in critically ill patients receiving high dose antibiotics, typically beta lactams [5,6]. Prospective studies have found the incidence of vitamin K deficiency as high as 25% among patients admitted to the intensive care unit, suggesting that severe systemic illness may predispose patients to potential coagulopathy[7].
ACCEPTED MANUSCRIPT This is a rare case that shows significant vitamin K deficiency coagulopathy developing within several days due to diarrhea. Vitamin K deficiency is likely under recognized and should be considered in patients with severely restricted diet or prolonged gastrointestinal losses.
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References
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SC
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[1] Vermeer C, Schurgers, LJ. A comprehensive review of vitamin K and vitamin K antagonists. Hematol Oncol Clin North Am 2000; 14:339. [2] Kumar R, Marwaha N, Marwaha R, et al. Vitamin K deficiency in diarrhoea. Indian J Pediatr. 2001 Mar:68(3):235-8. [3] Cavallaro R, Iovino P, Castiglione F, et al. Prevalence and clinical associations of prolonged prothrombin time in adult untreated coeliac disease. Eur J Gastroenterol Hepatol. 2004; 16:219223. [4] Krasinki S, Russell R, Kruger J, et al. Prevalence of vitamin K deficiency in chronic GI disorders. Am J Clin Nutrition. 41:639-643. [5] Robinson J, Banerjee R, Thiet M. Coagulopathy secondary to vitamin K deficiency in hyperemesis gravidarum. Obstet & Gynec. 1998 Mar;92(4)Supplement:673-675. [6] Ford S, Webb A, Payne R, et al. Iatrogenic vitamin K deficiency and life threatening coagulopathy BMJ Case Rep. 2008. [7] Crowther MA, McDonald E, Johnston M, et al. Vitamin K deficiency and D-dimer levels in the intensive care unit: a prospective cohort study. Blood Coagulation and Fibrinolysis 2002; 13(1): 49–52.
ACCEPTED MANUSCRIPT Table 1
168 mg/dL 31 mg/dL 1.1 mg/dL 9.4 mg/dL 135 mg/dL 4.5 mmol/L 111 mmol/L 7 mmol/L 22 28
Coagulation Tests PT PTT INR Fibrinogen D-dimer
118.9 seconds 59.3 seconds 11.2 629 mg/dL 1.74 mg/L
ED
PT CE
Hepatic Function Tests AST ALT Alkaline phosphatase GGT LDH Bilirubin Total Albumin Globulin Lipase
<3 unit/L 8 unit/L 61 until/L 34 unit/L 143 unit/L 0.2 mg/dL 2.6 gm/dL 5.1 gm/dL 149 unit/dL
Lactic Acid
1.7 mmol/L
Acetaminophen Salicylates
<2.0 mcg/mL <1.7 mg/dL
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Basic Metabolic Panel Glucose BUN Creatinine Calcium Sodium Potassium Chloride CO2 AGAP BUN/Cr ratio
SC
3.9 x10(3)/mcl 12.2 gm/dL 39.2% 622 x10(3)/mcl
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CBC White blood cell Hemoglobin Hematocrit Platelets
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S0735-6757(14)00762-1 doi: 10.1016/j.ajem.2014.10.028 YAJEM 54578
To appear in:
American Journal of Emergency Medicine
Received date: Accepted date:
15 September 2014 11 October 2014
Please cite this article as: Kelly Catherine, Sattler Steven, Schwartz Adam, Coagulopathy Secondary to Vitamin K Deficiency Caused by Severe Diarrhea, American Journal of Emergency Medicine (2014), doi: 10.1016/j.ajem.2014.10.028
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title: Coagulopathy Secondary to Vitamin K Deficiency Caused by Severe Diarrhea.
T
Authors: Catherine Kelly, DOa, Steven Sattler, DOa, Adam Schwartz, DOa a Good Samaritan Hospital Medical Center, 1000 Montauk Highway, West Islip, NY 11795
AC
CE
PT
ED
MA
NU
SC
Keywords: coagulopathy; vitamin K deficiency; diarrhea
RI P
Corresponding author: Catherine Kelly [email protected]; Good Samaritan Hospital Medical Center 1000 Montauk Highway, West Islip NY 11795; +16313764163
DIARRHEA INDUCING ACUTE VITAMIN K COAGULOPATHY
ACCEPTED MANUSCRIPT Introduction:
T
We describe a woman who presented to the emergency department (ED) due to severe diarrhea who had a significant coagulopathy secondary to depletion of vitamin K dependent clotting factors.
RI P
Case:
NU
SC
A 31 year old female currently under treatment for gastric cancer presented to the ED complaining of generalized weakness associated with abdominal cramping. The patient had been experiencing generalized, severe abdominal cramping, nausea, and diarrhea for the previous two weeks. Her bowel movements were profuse watery diarrhea and had increased in frequency and volume in the preceding days.
ED
MA
These symptoms began soon after initiation of chemotherapy with 5-fluorouracil and folinic acid for gastric carcinoma. She had a partial gastrectomy three months prior to presentation as the initial treatment of this malignancy. The patient was also four days post-op from an uncomplicated dilation and curettage for a missed abortion. At the time of the obstetrical procedure all laboratory tests, including coagulation studies, were known to be within normal limits.
CE
PT
The patient had no other significant chronic medical problems. Outpatient medications were limited to ondansetron and oxycodone prescribed after her dilation and curettage. The review of systems was pertinent for generalized weakness, nausea, diarrhea and abdominal pain. The patient denied any history of bruising, bleeding, petechiae or heavy menses. She denied any recent fevers or illness.
AC
The patient was afebrile with a pulse of 128, blood pressure of 124/88 mm Hg, respirations of 24 and a room air oxygen saturation of 99%. She appeared weak, diaphoretic and uncomfortable. Her abdomen was soft and tender to palpation periumbilically without guarding, rigidity, rebound, palpable organomegaly or masses. No skin lesions were noted. The remainder of physical exam was unremarkable. Morphine and ondansetron were administered for symptomatic relief. Laboratory results are listed in Table 1. A CT scan of the abdomen and pelvis with oral and intravenous contrast demonstrated no acute pathology. The patient was admitted to the intensive care unit with a metabolic acidosis, dehydration, and a profound coagulopathy. Her INR decreased from 11.2 to 1.7 within 24 hours after receiving 10 mg of phytonadione and 6 units of fresh frozen plasma. Mixing studies were performed which demonstrated full correction of the PT and PTT with dilution that was not time-dependent, ruling out presence of a clotting pathway inhibitor. The acidosis improved following rehydration and electrolyte replacement. She was treated with imipenem/cilastatin and metronidazole for presumed sepsis. All blood, stool and urine culture
ACCEPTED MANUSCRIPT results were negative. Over six days, the patient improved significantly and was subsequently discharged home for outpatient follow up with oncology.
T
Discussion:
RI P
Our case demonstrates a patient with the abrupt onset of a coagulopathy consistent with vitamin K deficiency. The coagulopathy was thought to be multifactorial due in part to malabsorption of dietary vitamin K and disruption of the normal gut flora which synthesize it due to chemotherapy related diarrhea.
MA
NU
SC
Vitamin K is a cofactor in multiple steps of the coagulation cascade. It is required for the synthesis of factors II, VII, IX and X. It impacts the intrinsic, extrinsic and common clotting pathways. Approximately 50% of vitamin K is obtained dietarily with absorption of phylloquinone (vitamin K1) in the proximal intestine and menadione and menaquinone (vitamin K2) absorbed in the lower intestine and colon. The remaining 50% is produced via bacterial synthesis by the gut flora [1]. Unlike most other vitamins, vitamin K is not stored in the body to any significant extent and it is estimated that a healthy person’s physiologic reserve is adequate for only one week.
PT
ED
Our patient developed a severely elevated PT and INR with mild elevation in PTT that was consistent with severe vitamin K deficiency. This condition was further supported by full correction of the PT/INR with mixing studies and clinical correction after receiving vitamin K. The patient’s PT/INR was known to be normal 4 days prior to this ED evaluation at the time of her D&C, which is supportive that this was an acute process and not a chronic condition.
AC
CE
We believe her acute coagulopathy was not part of a sepsis syndrome because she remained afebrile without leukocytosis and negative cultures. Disseminated intravascular coagulation related to the recent missed abortion was ruled out because of elevated fibrinogen, normal platelets, and only mild elevation of the PTT. Development of vitamin K related coagulopathy secondary to diarrhea has long been recognized in pediatrics. Children with acute and intractable diarrhea have been shown to have increased PT and higher rates of clinically significant hemorrhage [2]. These symptoms may be related to inadequate intake, insufficient absorption and/or decreased synthesis due to changes in gut flora. However, this phenomenon has not been well described in the adult patients. Patients with chronic gastrointestinal disorders such as Crohn’s disease, may develop coagulopathy, but it typically requires a more prolonged course. Studies show that up to 46% of patients with untreated Crohn’s disease have mild vitamin K deficiency, while 18.5% have prolongation of PT [3,4]. In adults, case reports show development of similar coagulopathy has occurred in patients with hyperemesis gravidarum, pancreatic insufficiency, and in critically ill patients receiving high dose antibiotics, typically beta lactams [5,6]. Prospective studies have found the incidence of vitamin K deficiency as high as 25% among patients admitted to the intensive care unit, suggesting that severe systemic illness may predispose patients to potential coagulopathy[7].
ACCEPTED MANUSCRIPT This is a rare case that shows significant vitamin K deficiency coagulopathy developing within several days due to diarrhea. Vitamin K deficiency is likely under recognized and should be considered in patients with severely restricted diet or prolonged gastrointestinal losses.
T
References
AC
CE
PT
ED
MA
NU
SC
RI P
[1] Vermeer C, Schurgers, LJ. A comprehensive review of vitamin K and vitamin K antagonists. Hematol Oncol Clin North Am 2000; 14:339. [2] Kumar R, Marwaha N, Marwaha R, et al. Vitamin K deficiency in diarrhoea. Indian J Pediatr. 2001 Mar:68(3):235-8. [3] Cavallaro R, Iovino P, Castiglione F, et al. Prevalence and clinical associations of prolonged prothrombin time in adult untreated coeliac disease. Eur J Gastroenterol Hepatol. 2004; 16:219223. [4] Krasinki S, Russell R, Kruger J, et al. Prevalence of vitamin K deficiency in chronic GI disorders. Am J Clin Nutrition. 41:639-643. [5] Robinson J, Banerjee R, Thiet M. Coagulopathy secondary to vitamin K deficiency in hyperemesis gravidarum. Obstet & Gynec. 1998 Mar;92(4)Supplement:673-675. [6] Ford S, Webb A, Payne R, et al. Iatrogenic vitamin K deficiency and life threatening coagulopathy BMJ Case Rep. 2008. [7] Crowther MA, McDonald E, Johnston M, et al. Vitamin K deficiency and D-dimer levels in the intensive care unit: a prospective cohort study. Blood Coagulation and Fibrinolysis 2002; 13(1): 49–52.
ACCEPTED MANUSCRIPT Table 1
168 mg/dL 31 mg/dL 1.1 mg/dL 9.4 mg/dL 135 mg/dL 4.5 mmol/L 111 mmol/L 7 mmol/L 22 28
Coagulation Tests PT PTT INR Fibrinogen D-dimer
118.9 seconds 59.3 seconds 11.2 629 mg/dL 1.74 mg/L
ED
PT CE
Hepatic Function Tests AST ALT Alkaline phosphatase GGT LDH Bilirubin Total Albumin Globulin Lipase
<3 unit/L 8 unit/L 61 until/L 34 unit/L 143 unit/L 0.2 mg/dL 2.6 gm/dL 5.1 gm/dL 149 unit/dL
Lactic Acid
1.7 mmol/L
Acetaminophen Salicylates
<2.0 mcg/mL <1.7 mg/dL
AC
RI P
Basic Metabolic Panel Glucose BUN Creatinine Calcium Sodium Potassium Chloride CO2 AGAP BUN/Cr ratio
SC
3.9 x10(3)/mcl 12.2 gm/dL 39.2% 622 x10(3)/mcl
MA
CBC White blood cell Hemoglobin Hematocrit Platelets
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R es u lt
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L ab